Soft Tissues: Alveolar rhabdomyosarcoma with t(1;13)(p36;q14) PAX7/FOXO1

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Soft Tissues: Alveolar rhabdomyosarcoma with t(1;13)(p36;q14) PAX7/FOXO1

Written	2010-07	Frederic G Barr
		Department of Pathology, Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C470-C476,C478-C479,C490-C496,C498-C499 CONNECTIVE & SOFT TISSUE

ICD-Morpho 8920/3 Alveolar rhabdomyosarcoma

Atlas_Id 5012

Phylum Soft Tissues::Alveolar rhabdomyosarcoma

Clinics and Pathology

Phenotype / cell stem origin Generally found in alveolar rhabdomyosarcoma (ARMS); also found in rare cases diagnosed as embryonal rhabdomyosarcoma (ERMS).

Epidemiology Occurs in ~20% ARMS cases and <5% of ERMS cases: patients tend to be younger children compared to those with t(2;13)-positive ARMS tumors.

Clinics Tumors tend to show lower invasiveness compared to those with t(2;13)-positive ARMS tumors. In metastatic cases, there is a low incidence of bone marrow involvement.

Prognosis In one study, patients with localized t(2;13) and t(1;13)-positive ARMS had comparable outcomes whereas a recent study with small numbers suggested that localized t(1;13) tumors had a better outcome than those with localized t(2;13) tumors. Among patients presenting with metastatic disease, those with t(1;13)-positive tumors had a significantly better outcome than those with t(2;13)-positive tumors. Note: these studies are based on molecular detection of the translocations.

Cytogenetics

Cytogenetics
Morphological Though a balanced 1;13 is sometimes visible in cases with the associated molecular fusion event, in many cases the balanced translocation is not visible. Instead the molecular fusion is found associated with a subsequent amplification event, usually double minute chromosomes.

Diagram of t(1;13)(p36;q14) chromosomal translocation.

Cytogenetics Molecular The product of the 1;13 translocation is amplified in ~90% of t(1;13)-positive cases. Amplification events involving 2p24 and 13q31 (as determined by DNA-based array studies).

Genes involved and Proteins

Gene Name PAX7

Location 1p36

Protein Transcription factor - paired box (PAX) family.

Gene Name FOXO1

Location 13q14

Protein Transcription factor - forkhead box (FOX) family.

Result of the chromosomal anomaly

Hybrid Gene
Description The 1;13 translocation breaks within intron 7 of the PAX7 gene and intron 1 of the FOXO1 gene on chromosome 13 to generate a PAX7-FOXO1 fusion gene as well as a reciprocal FOXO1-PAX7 fusion gene. In ~55% of PAX7-FOXO1-positive ARMS tumors, this FOXO1-PAX3 gene is not detectable. In cases with fusion gene amplification, the PAX7-FOXO1 fusion gene is amplified whereas the reciprocal FOXO1-PAX7 fusion gene is not.

Transcript The PAX7-FOXO1 fusion transcript consists of the first 7 exons of PAX3 fused to FOXO1 exons 2 and 3. There is evidence that the PAX7-FOXO1 fusion transcript is upregulated relative to the wild-type PAX7 transcript, presumably due to increased copy number of the fusion gene by amplification.

Fusion Protein
Description The fusion gene has a 2484 nt open reading frame encoding an 828 amino acid fusion protein. This fusion protein is a transcription factor with a PAX7 DNA binding domain and FOXO1 transactivation domain.

Expression Localisation Nuclear.

Oncogenesis Transcription dysregulation. At the cellular level there is evidence of alterations in control of growth. In conjunction with other genetic changes, recipient cells show transformation in culture and tumorigenesis in injected mice.

Bibliography

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Genomic and clinical analyses of 2p24 and 12q13-q14 amplification in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group.

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In vivo amplification of the PAX3-FKHR and PAX7-FKHR fusion genes in alveolar rhabdomyosarcoma.

Barr FG, Nauta LE, Davis RJ, Schafer BW, Nycum LM, Biegel JA.

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Examination of gene fusion status in archival samples of alveolar rhabdomyosarcoma entered on the Intergroup Rhabdomyosarcoma Study-III trial: a report from the Children's Oncology Group.

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Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma.

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PAX3 and PAX7 exhibit conserved cis-acting transcription repression domains and utilize a common gain of function mechanism in alveolar rhabdomyosarcoma.

Bennicelli JL, Advani S, Schafer BW, Barr FG.

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Chromosomal translocation t(1;13)(p36;q14) in a case of rhabdomyosarcoma.

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Fusion genes resulting from alternative chromosomal translocations are overexpressed by gene-specific mechanisms in alveolar rhabdomyosarcoma.

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Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma.

Davis RJ, D'Cruz CM, Lovell MA, Biegel JA, Barr FG.

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Du S, Lawrence EJ, Strzelecki D, Rajput P, Xia SJ, Gottesman DM, Barr FG.

Int J Cancer. 2005 May 20;115(1):85-92.

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Structural analysis of PAX7 rearrangements in alveolar rhabdomyosarcoma.

Fitzgerald JC, Scherr AM, Barr FG.

Cancer Genet Cytogenet. 2000 Feb;117(1):37-40.

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Concomitant amplification and expression of PAX7-FKHR and MYCN in a human rhabdomyosarcoma cell line carrying a cryptic t(1;13)(p36;q14).

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Med Pediatr Oncol. 2001 Feb;36(2):259-67.

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Clinical aspects of alveolar rhabdomyosarcoma with translocation t(1;13)(p36;q14) and hypotetraploidy.

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Pax3-fkhr and pax7-fkhr fusion genes impact outcome of alveolar rhabdomyosarcoma in children.

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Use of a novel FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of alveolar rhabdomyosarcoma.

Nishio J, Althof PA, Bailey JM, Zhou M, Neff JR, Barr FG, Parham DM, Teot L, Qualman SJ, Bridge JA.

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Correlation between histology and PAX/FKHR fusion status in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group.

Parham DM, Qualman SJ, Teot L, Barr FG, Morotti R, Sorensen PH, Triche TJ, Meyer WH; Soft Tissue Sarcoma Committee of the Children's Oncology Group.

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Citation

This paper should be referenced as such :

Barr, FG

Soft tissue tumors: t(1;13)(p36;q14) in alveolar rhabdomyosarcoma

Atlas Genet Cytogenet Oncol Haematol. 2011;15(4):378-380.

Free journal version : [ pdf ] [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/t113p36q14AlvRhabdoID5012.html

Other genes implicated (Data extracted from papers in the Atlas) [ 3 ]

Genes EWSR1 FOXO1 PAX3

Translocations implicated (Data extracted from papers in the Atlas)

t(1;13)(p36;q14) PAX7/FOXO1

External links

Mitelman database t(1;13)(p36;q14) PAX7/FOXO1 [Case List]    t(1;13)(p36;q14) PAX7/FOXO1 [Association List] Mitelman database (CGAP - NCBI)

arrayMap Topo ( C47,C49) arrayMap ((UZH-SIB Zurich) [auto + random 100 samples .. if exist ] [tabulated segments]

COSMIC_fusion PAX7 (1p36.13) FOXO1 (13q14.11)    [fusion287] [fusion288] [fusion344]
Mitelman database PAX7/FOXO1[MCList]    PAX7 (1p36.13) FOXO1 (13q14.11)

Mitelman database PAX7/FOXO1[MCList]    PAX7 (1p36.13) FOXO1 (13q14.11)   t(1;13)(p36;q14)

Disease database Soft Tissues: Alveolar rhabdomyosarcoma with t(1;13)(p36;q14) PAX7/FOXO1

REVIEW articles automatic search in PubMed

Last year articles automatic search in PubMed

Home Genes Leukemias Solid Tumors Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.

ICD-Topo	C470-C476,C478-C479,C490-C496,C498-C499 CONNECTIVE & SOFT TISSUE
ICD-Morpho	8920/3 Alveolar rhabdomyosarcoma
Atlas_Id	5012
Phylum	Soft Tissues::Alveolar rhabdomyosarcoma

Phenotype / cell stem origin	Generally found in alveolar rhabdomyosarcoma (ARMS); also found in rare cases diagnosed as embryonal rhabdomyosarcoma (ERMS).
Epidemiology	Occurs in ~20% ARMS cases and <5% of ERMS cases: patients tend to be younger children compared to those with t(2;13)-positive ARMS tumors.
Clinics	Tumors tend to show lower invasiveness compared to those with t(2;13)-positive ARMS tumors. In metastatic cases, there is a low incidence of bone marrow involvement.
Prognosis	In one study, patients with localized t(2;13) and t(1;13)-positive ARMS had comparable outcomes whereas a recent study with small numbers suggested that localized t(1;13) tumors had a better outcome than those with localized t(2;13) tumors. Among patients presenting with metastatic disease, those with t(1;13)-positive tumors had a significantly better outcome than those with t(2;13)-positive tumors. Note: these studies are based on molecular detection of the translocations.

Cytogenetics Morphological	Though a balanced 1;13 is sometimes visible in cases with the associated molecular fusion event, in many cases the balanced translocation is not visible. Instead the molecular fusion is found associated with a subsequent amplification event, usually double minute chromosomes.


	Diagram of t(1;13)(p36;q14) chromosomal translocation.

Cytogenetics Molecular	The product of the 1;13 translocation is amplified in ~90% of t(1;13)-positive cases. Amplification events involving 2p24 and 13q31 (as determined by DNA-based array studies).

Gene Name	PAX7
Location	1p36
Protein	Transcription factor - paired box (PAX) family.

Gene Name	FOXO1
Location	13q14
Protein	Transcription factor - forkhead box (FOX) family.

Hybrid Gene
Description	The 1;13 translocation breaks within intron 7 of the PAX7 gene and intron 1 of the FOXO1 gene on chromosome 13 to generate a PAX7-FOXO1 fusion gene as well as a reciprocal FOXO1-PAX7 fusion gene. In ~55% of PAX7-FOXO1-positive ARMS tumors, this FOXO1-PAX3 gene is not detectable. In cases with fusion gene amplification, the PAX7-FOXO1 fusion gene is amplified whereas the reciprocal FOXO1-PAX7 fusion gene is not.
Transcript	The PAX7-FOXO1 fusion transcript consists of the first 7 exons of PAX3 fused to FOXO1 exons 2 and 3. There is evidence that the PAX7-FOXO1 fusion transcript is upregulated relative to the wild-type PAX7 transcript, presumably due to increased copy number of the fusion gene by amplification.
Fusion Protein
Description	The fusion gene has a 2484 nt open reading frame encoding an 828 amino acid fusion protein. This fusion protein is a transcription factor with a PAX7 DNA binding domain and FOXO1 transactivation domain.
Expression Localisation	Nuclear.
Oncogenesis	Transcription dysregulation. At the cellular level there is evidence of alterations in control of growth. In conjunction with other genetic changes, recipient cells show transformation in culture and tumorigenesis in injected mice.

Mitelman database	t(1;13)(p36;q14) PAX7/FOXO1 [Case List] t(1;13)(p36;q14) PAX7/FOXO1 [Association List] Mitelman database (CGAP - NCBI)
arrayMap	Topo ( C47,C49) arrayMap ((UZH-SIB Zurich) [auto + random 100 samples .. if exist ] [tabulated segments]

COSMIC_fusion	PAX7 (1p36.13) FOXO1 (13q14.11) [fusion287] [fusion288] [fusion344]
Mitelman database	PAX7/FOXO1[MCList] PAX7 (1p36.13) FOXO1 (13q14.11)
Mitelman database	PAX7/FOXO1[MCList] PAX7 (1p36.13) FOXO1 (13q14.11) t(1;13)(p36;q14)

Disease database	Soft Tissues: Alveolar rhabdomyosarcoma with t(1;13)(p36;q14) PAX7/FOXO1

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed